We have described a new approach to selective drug delivery which has the potential of enhancing the tumor incorporation of anticancer drugs while reducing systemic drug toxicity. The basis of this method is to use of temperature-sensitive liposomes as drug-carriers which can be made to release their contents rapidly and completely in a locally heated region of the body. By this approach we have obtained a ratio of 14:1 between methotrexate (MTX) uptake in heated and non-heated solid mouse tumors (L1210) and have delayed growth of the tumor more than can be explained by the sum of separate treatments with heat and liposomal MTX. In the proposed research the techniques used for the local heating of tumors (microwave and water bath) will be refined. The mecanism of drug release from temperature-sensitive liposomes will be investigated as the basis for improving previously observed results with MTX and for the rational design of additional liopsome/drug combinations. The pharmacology of drug plasma clearance and tissue distribution will be studied in vivo using radiotracers, initially with 3H-MTX but subsequently with other drugs as encapsulation methods are developed. The chemotherapeutic effectiveness of our liposome/drug preparations will be tested against the growth of solid Lewis lung and L1210 tumors in mice. These studies should considerably increase our understanding of this new approach to selective drug delivery.